Novel mutation in GNAO1 gene causes a distinct phenotype of borderline-mild intellectual disability and rolandic epilepsy with EEG pattern of ESES.
2Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3Pediatric Metabolic Disease Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer, Israel
4Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
5Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel
GNAO1 mutations are traditionally considered one of the many genetic causes of early onset epileptic encephalopathy. De novo heterozygous mutations in GANO1 are reported to cause severe neurodevelopmental disorder, profound cognitive dysfunction and occasionally, movement disorder.
We report here on six individuals from two related families (the mother of family A and father of family B are siblings), who harbour a new heterozygous GNAO1 variant (p.Met1Val; c.1A>G) with much milder and distinct clinical phenotype. This sequence change affects the initiator methionine of the GNAO1 mRNA.
Three siblings to non-consanguineous parents in family A, presented with rolandic epilepsy between 4-6 years of age, EEG pattern consistent with electrical status epilepticus in sleep (ESES) and borderline-mild intellectual disability. It is noteworthy that early development was reported as normal and they feature normal tone on neurologic examination with no movement disorders. Two of the affected siblings and the affected mother harbour the p.Met1Val variant identified through research-based exome sequencing. The third affected sibling has not been tested yet.
Three siblings to non-consanguineous parents in family B, presented with a phenotype similar to family A along with speech dyspraxia. Two of the affected siblings and the healthy father harbour the p.Met1Val variant identified through epilepsy panel. The third affected sibling has not been tested yet.
In summary, we report a new GNAO1 variant with milder unique phenotype and incomplete penetrance pattern of inheritance which has not been reported yet in relation to GNAO1 mutations. Additionally, this variant may broaden the genetic landscape of ESES.